The goal of this proposal is to provide the Principal Investigator, John K. Neubert, DDS, PhD, with the opportunity to develop as an independent translational pain researcher. Dr. Neubert has completed a dental residency in orofacial pain management and a PhD in Oral Biology at UCLA and is finishing a clinical research fellowship at the NIH. Additional experience in fundamental molecular and cellular biology is required to provide the principal investigator with the requisite skills needed for this translational research. This experience will be acquired during the Scholar Development Phase and will complement the Principal Investigator's prior in vivo physiological and clinical pain research experiences. This phase will be supervised by Dr. Michael Iadarola at the NIH, who has over 20 years of experience and continues to excel in the areas of molecular and cellular pain biology. Dr. Neubert will receive full institutional support during the Scholar Development Phase from the NIDCR, NIH, including use of facilities, equipment, and support staff. The Faculty Transition Phase will be critical for the principal investigator to become an innovative and independent researcher. [unreadable] [unreadable] Chronic pain continues to affect a countless number of individuals and costs society billions of dollars each year. The vanilloid-1 receptor (VR1) provides an excellent target for analgesia due to its prominent role in inflammation and hyperalgesia. The long-range goal is to investigate the peripheral actions of VR1. The objective is to elucidate the role of VR1 through specific ultrapotent agonists and antagonists designed to induce or block neuronal cells expressing this receptor in vitro, and to evaluate these agents in vivo. The central hypothesis of the proposed research is that peripheral VR1 activity is necessary to effectively transduce painful stimuli. Three Specific Aims will be investigated: Aim #1, Pharmacologically characterize the function of the VR1 -ionophore; Aim #2, Evaluate the analgesic efficacy of vanilloid receptor agonists in models of acute pain; Aim #3, Clinically evaluate the analgesic efficacy of vanilloid receptor agonists for acute and chronic orofacial pain conditions. These aims will be tested by an experimental approach using VRl-transfected cell lines and evaluating their inhibition by chemical compounds screened from combinatorial libraries. Additionally, peripheral application of the potent VR1 agonist, resiniferatoxin (RTX), will be tested in vivo through a number of behavioral and histological assessments to determine if vanilloids are effective in blocking pain. Lastly, RTX will be evaluated for analgesic efficacy in human models of acute and chronic pain. Completion of the proposed studies is expected to provide a better understanding of the mechanisms responsible for contributing to clinical pain, thus leading to development of mechanistically-derived therapies. These outcomes are expected to have significant positive effects on a wide spectrum of pain relating to tissue damage and injury. [unreadable] [unreadable]